EP2906530A1 - Processes for the synthesis of 2-amino-4,6-dimethoxybenzamide and other benzamide compounds - Google Patents
Processes for the synthesis of 2-amino-4,6-dimethoxybenzamide and other benzamide compoundsInfo
- Publication number
- EP2906530A1 EP2906530A1 EP13779704.9A EP13779704A EP2906530A1 EP 2906530 A1 EP2906530 A1 EP 2906530A1 EP 13779704 A EP13779704 A EP 13779704A EP 2906530 A1 EP2906530 A1 EP 2906530A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dimethoxyaniline
- compound
- agent
- process according
- produce
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 104
- LSDUYZHWQMMNCO-UHFFFAOYSA-N 2-amino-4,6-dimethoxybenzamide Chemical compound COC1=CC(N)=C(C(N)=O)C(OC)=C1 LSDUYZHWQMMNCO-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 230000008569 process Effects 0.000 title claims description 87
- 238000003786 synthesis reaction Methods 0.000 title abstract description 19
- 230000015572 biosynthetic process Effects 0.000 title abstract description 14
- 150000003936 benzamides Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 125000006239 protecting group Chemical group 0.000 claims abstract description 51
- 239000001257 hydrogen Substances 0.000 claims abstract description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 39
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 93
- WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 claims description 92
- 238000006243 chemical reaction Methods 0.000 claims description 89
- 230000002140 halogenating effect Effects 0.000 claims description 57
- 230000000887 hydrating effect Effects 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- 230000001376 precipitating effect Effects 0.000 claims description 42
- 239000003223 protective agent Substances 0.000 claims description 35
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 31
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 31
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 239000002244 precipitate Substances 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 239000012351 deprotecting agent Substances 0.000 claims description 15
- 238000001556 precipitation Methods 0.000 claims description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 14
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 5
- 238000005580 one pot reaction Methods 0.000 claims description 5
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 11
- 150000008064 anhydrides Chemical class 0.000 claims 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 229940054066 benzamide antipsychotics Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 239000002904 solvent Substances 0.000 description 51
- 239000000243 solution Substances 0.000 description 50
- MMLLIZJCTNVTMW-UHFFFAOYSA-N 2-amino-4,6-dimethoxybenzonitrile Chemical compound COC1=CC(N)=C(C#N)C(OC)=C1 MMLLIZJCTNVTMW-UHFFFAOYSA-N 0.000 description 36
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 125000005843 halogen group Chemical group 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- -1 methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, pentoxy, n-hexyloxy Chemical group 0.000 description 12
- 239000003518 caustics Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 125000004093 cyano group Chemical group *C#N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000000524 functional group Chemical group 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 8
- 238000013019 agitation Methods 0.000 description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 7
- 229940011051 isopropyl acetate Drugs 0.000 description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000000306 component Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000012296 anti-solvent Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- UZEFANXQRVBAGI-UHFFFAOYSA-N 5,7-dimethoxy-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C=2C1=CC(OC)=CC=2OC UZEFANXQRVBAGI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical class NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 229910014265 BrCl Inorganic materials 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000010936 aqueous wash Methods 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 239000002327 cardiovascular agent Substances 0.000 description 2
- 229940125692 cardiovascular agent Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011067 equilibration Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000001226 reprecipitation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- HZBQKANLOSWJLU-UHFFFAOYSA-N 2-amino-4,6-dimethoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C(OC)=C1 HZBQKANLOSWJLU-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- FAMGTYWNHVETJC-UHFFFAOYSA-N 4,6-dimethoxy-1h-indole-2,3-dione Chemical compound COC1=CC(OC)=CC2=C1C(=O)C(=O)N2 FAMGTYWNHVETJC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- CIYHWDJHJHPIRU-UHFFFAOYSA-N NC1=C(C#N)C(=CC(=C1)OC)OC.NC1=C(C#N)C(=CC(=C1)OC)OC Chemical compound NC1=C(C#N)C(=CC(=C1)OC)OC.NC1=C(C#N)C(=CC(=C1)OC)OC CIYHWDJHJHPIRU-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- LEKPFOXEZRZPGW-UHFFFAOYSA-N copper;dicyanide Chemical compound [Cu+2].N#[C-].N#[C-] LEKPFOXEZRZPGW-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- PANJMBIFGCKWBY-UHFFFAOYSA-N iron tricyanide Chemical compound N#C[Fe](C#N)C#N PANJMBIFGCKWBY-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- NLEUXPOVZGDKJI-UHFFFAOYSA-N nickel(2+);dicyanide Chemical compound [Ni+2].N#[C-].N#[C-] NLEUXPOVZGDKJI-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- SOWBFZRMHSNYGE-UHFFFAOYSA-N oxamic acid Chemical class NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to processes for the synthesis of 2-amino-4,6- dimethoxybenzamide and other benzamide compounds.
- 2-Amino-4,6-dimethoxybenzamide has been prepared from 4,6-dimethoxyisatoic anhydride.
- the 4,6-dimethoxyisatoic anhydride was, in turn, prepared by a reaction of 4,6- dimethoxyanthranilic acid with phosgene (U.S. Patent No. 4,191,840 and Org. Synth. 1947, 27, 45).
- a different route converts 3,5-dimethoxyaniline to its hydrochloride salt, after which the salt is reacted with oxalyl chloride to give 4,6-dimethoxyisatin.
- the isatin is converted to the target compound via an unstable carboxyl intermediate by reaction with sodium hydroxide and hydrogen peroxide followed by an EDCI/HOBt-mediated coupling to produce 2-amino-4,6- dimethoxybenzamide (WO 2008/92231).
- This invention meets the above-identified needs by providing processes for producing at least one
- R 1 and R 5 each independently represent a hydrogen, a Ci-C 6 alkyl, a hydroxy, or a Ci-C 6 alkoxy;
- R , R , and R each independently represent a hydrogen, a Ci-C 6 alkyl, or a Ci-C 6 alkoxy;
- R 6 and R 7 each independently represent a hydrogen, a Ci-C 6 alkyl, a protecting group, or a directing group;
- X represents a halo moiety or a halo-like moiety; wherein at least one of R 1 and R 5 represent a hydrogen;
- R represents a protecting group or a directing group
- step (ii) the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a CrC 6 alkyl, or
- the at least one Compound IV is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a Ci-C 6 alkyl.
- This invention also meets the above-identified needs by providing processes for producing at least one
- R 1 and R 5 each independently represent a hydrogen, a CrC 6 alkyl, a hydroxy, or a CrC 6 alkoxy;
- R , R , and R each independently represent a hydrogen, a Ci-C 6 alkyl, or a Ci-C 6 alkoxy;
- R 6 and R 7 each independently represent a hydrogen, a CrC 6 alkyl, a protecting group, or a directing group
- X represents a halo moiety or a halo-like moiety
- R 1 and R 5 represent a hydrogen
- R represents a protecting group or a directing group
- step (ii) the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a Ci-C 6 alkyl, or
- the at least one Compound IV is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a CrC 6 alkyl.
- step (iv) the at least one Compound IV is combined with at least one second precipitating agent to precipitate the at least one Compound IV.
- the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a Ci-C 6 alkyl and the at least one Compound III is combined with at least one third precipitating agent to precipitate the at least one Compound III.
- At least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a CrC 6 alkyl and the at least one Compound IV is combined with at least one third precipitating agent to precipitate the at least one Compound IV.
- R 1 and R 5 each independently represent a hydrogen, a Ci-C 6 alkyl, a
- R , R , and R each independently represent a hydrogen, a Ci-C 6 alkyl, or a Ci-C 6 alkoxy; and R 6 and R 7 each independently represent a hydrogen or a Ci-C 6 alkyl.
- X represents a halo moiety or a halo-like moiety.
- At least one of R 1 , R 2 , R 3 , R 4 , or R 5 represents a Ci-C 6 alkoxy.
- At least two of R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a Ci-C 6 alkoxy.
- At least three of R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a Ci-C 6 alkoxy.
- R 2 and R 4 each independently represent a Ci-C 6 alkoxy
- R 1 and R 3 each represent a hydrogen.
- the Ci-C 6 alkoxy is a methoxy.
- R 2 and R 4 each independently represent a Ci-C 6 alkoxy
- R 1 and R3 each represent a hydrogen
- R 7 represents trifluoroacetyl
- a process according to this invention comprises:
- a process according to this invention comprises:
- a process according to this invention comprises:
- a process according to this invention comprises:
- cyano or "nitrile” refers to a -CN.
- halo moiety or halo-like moiety refers to chloro (CI), bromo (Br), iodo (I), triflate (-OTf), tosylate (-OTs), or mesylate (-OMs).
- alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon.
- hydroxy refers to a hydroxyl (-OH) moiety.
- alkoxy refers to an alkyl moiety having an oxygen moiety attached thereto, e.g. methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, pentoxy, n-hexyloxy and the like.
- intermediate refers to any of Compounds II, III, or IV.
- the invention provides processes for precipitating and/or re- precipitating at least one intermediate produced in the synthesis of Compound I.
- the invention also provides a process for the synthesis of Compound I comprising conducting two or more of the process steps in a one-pot process.
- the steps of protecting, halogenating, cyanating, and deprotecting, as described herein, are carried out in a one-pot process.
- FIG. 1 is an illustration of a process according to this invention for the preparation of 2- amino-4,6-dimethoxybenzamide.
- FIG. 2 is another illustration of a process according to this invention for the preparation of 2-amino-4,6-dimethoxybenzamide.
- the process step wherein at least one Compound II is produced by a process comprising combining at least one Compound V with at least one protecting agent to produce at least one Compound II can be referred to as a "protecting step.”
- Protecting agent refers to any compound or groups of compounds that protects functional groups from unwanted reactions.
- the protecting agent can protect R 5 of compound V during production of Compound II, or can protect R 5 of compound II during the halogenating step.
- Protecting group refers to a protecting agent or part of a protecting agent that is attached to Compounds II, III, IV, or I.
- a protecting group selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
- Certain processes of this invention rely upon the protective groups to block reactive nitrogen present in the reactants.
- the protecting group exhibits the following characteristics: (i) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; (ii) is selectively removable from the protected substrate to yield the desired functionality; and (iii) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions.
- “Directing group” refers to a protecting agent or part of a protecting agent that influences the reactivity of a compound such that a chemical reaction involving the compound can occur with altered regio selectivity of the compound.
- a wide variety of protecting groups/directing groups are known to those skilled in the art of organic synthesis.
- Non-limiting examples of suitable protecting groups/directing groups can be found in Wuts et al. (2007) Greene's Protective Groups in Organic Synthesis, 4th Ed. (John Wiley & Sons, Inc., New York).
- amino-protecting group and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures.
- a protecting agent one skilled in the art would understand which portion of the protecting agent will be attached, i.e. the protecting group, to the compound to be protected.
- a protecting group one skilled in the art could deduce the necessary protecting agent to achieve the resulting protecting group.
- trifluoroacetic anhydride may be referred to as the protecting agent and trifluoroacetyl is the protecting group.
- an acid chloride may be referred to as the protecting agent; for example benzoyl chloride can be referred to as the protecting agent, in which case benzoyl is the protecting group.
- protecting group “protecting group”, “directing group”, “protective group”, or “protecting agent” may be used interchangeably and one skilled in the art would understand the relationship of the protecting agent to the protecting group or directing group.
- a protecting agent it includes all of the resulting protecting group or directing group and when referring to a protecting group or directing group, it also includes all of the protecting agent to create the resulting protecting group.
- Non-limiting exemplary protecting agent or its corresponding protecting groups or directing groups include acetyl, monohaloacetyl, dihaloacetyl, and trihaloacetyl (wherein the halo moiety may be the same or different for each dihaloacetyl and trihaloacetyl group), acetamido, benzyl (Bn), benzoyl (Bz), benzyloxycarbonyl
- protecting group refers to a compound where at least one of its functional group is a protecting group or a directing group.
- the protecting group or directing group is an acetyl. [0041] In another embodiment, the protecting group or directing group is a monohaloacetyl.
- the protecting group or directing group is a dihaloacetyl.
- the protecting group or directing group is a trihaloacetyl.
- the protecting group or directing group is trifluoro acetyl. It has been discovered that the trifluoroacetyl protecting/directing group results in an improved selectivity over the acetyl protecting/directing group during the halogenating step.
- the preparation for the synthesis of Compound I comprises combining Compound V with at least one protecting agent to produce a protected Compound II. It is to be understood that one skilled in the art of organic synthesis could follow the methods described or exemplified herein to determine if providing an already protected Compound II, or protecting a Compound V to produce a protected Compound II, is necessary to synthesize Compound I.
- the protecting step reaction can be carried out under any reaction time, pressure, temperature, solvent, pH condition, concentration, reagents ratio/amount, and any other chemical reaction conditions that are suitable to provide the desired protecting/directing effect. It is understood that one skilled in the art, given the teachings of this specification, can determine and/or optimize the reaction time, pressure, temperature, solvent, pH condition, concentration, reagent ratio/amount, and any other chemical reaction conditions suitable for the protecting step.
- Compound I is 2-amino-4,6-dimethoxybenzamide and Compound V is 3,5-dimethoxyaniline.
- the synthesis of 2-amino-4,6-dimethoxybenzamide comprises protecting 3,5-dimethoxyaniline with at least one protecting agent to produce a protected Compound II.
- the protecting step in this example comprises combining 3,5-dimethoxyaniline with
- Methyl tertiary-butyl ether can be used as a solvent in place of, or in addition to, toluene.
- Other suitable solvents may also be used. Given the teachings of this disclosure, one skilled in the art can select one or more other suitable solvents.
- a solution comprising the toluene or other solvent is taken directly to the next step, i.e. the halogenating step, following aqueous washes.
- a solution comprising the toluene or other solvent is taken directly to the next step, i.e. the halogenating step, without any aqueous washes.
- one skilled in the art may remove, reduce, or increase the toluene or other solvent and/or other intermediates, and/or remove water before halogenating Compound II, e.g. removal of water via azeotropic distillation of the toluene or other solvent and water.
- the process step wherein at least one Compound III is produced by a process comprising combining at least one Compound II with at least one halogenating agent to produce at least one Compound III can be referred to as the halogenating step.
- Halogenating agent refers to any compound that is capable of reacting with
- Halo-like moiety refers to any group that behaves similarly to a halo moiety in terms of reactivity.
- halo-like moieties include triflate (-OTf), mesylate (-OMs), and tosylate (-OTs).
- halogenating agents include I 2 , IC1, IC1 3 , IBr, Br 2 , BrCl, Cl 2 , N-chlorosuccinimide, N-bromosuccinimide (NBS), l,3-dibromo-5,5-dimethylhydantoin (DBDMH), TsCl, tosyl anhydride, MsCl, triflic chloride, and triflic anhydride.
- NSS N-chlorosuccinimide
- N-bromosuccinimide N-bromosuccinimide
- DBDMH l,3-dibromo-5,5-dimethylhydantoin
- TsCl tosyl anhydride
- MsCl triflic chloride
- triflic anhydride triflic anhydride.
- the amount of halogenating agent used should be stoichiometric with the desired product, as will be familiar to those skilled in the art.
- the halogenating agent is NBS.
- the halogenating agent is N-chlorosuccimimide.
- the halogenating agent is DBDMH.
- the halogenating agent is selected from I 2 , IC1, IC1 3 , IBr, Br 2 , BrCl, and Cl 2 .
- the halogenating agent is selected from TsCl, tosyl anhydride, MsCl, triflic chloride, and triflic anhydride.
- the halogenating step may be carried out at any temperature range above the freezing point and below the boiling point of the selected solvent. It is desirable to optimize the temperature and solvent conditions in accordance with solubility considerations of the Compound II when subjected to the halogenating agent.
- the temperature range is from about -65 °C to about 100 °C.
- the temperature range is from about -65 °C to about 50 °C.
- the temperature range is from about -65 °C to about 10 °C.
- the temperature range is from about -10 °C to about 10 °C.
- the temperature range is from about -10 °C to about 5 °C.
- the temperature range is from about -5 °C to about 5 °C.
- the temperature range is from about 0 °C to about 5 °C.
- the protected aniline (3,5- dimethoxytrifluoroacetanilide) compound is reacted with at least one halogenating agent as shown, N-bromosuccinimide (NBS), at a temperature range from about -5 °C to 0 °C to produce halo isomers (e.g. bromo-3,5-dimethoxytrifluoroacetanilide isomers).
- NBS N-bromosuccinimide
- the halogenating step solvent can comprise toluene.
- MtBE and/or dimethylacetamide (DMAc) can be used as a halogenating step solvent in place of, or in addition to, toluene.
- DMAc dimethylacetamide
- Other suitable halogenating step solvents can also be used. Given the teachings of this disclosure, one skilled in the art can select one or more other suitable solvents.
- the halogenating step produces various halo isomers.
- the halogenating step can produce isomers wherein the halo, or as shown, the bromo, is at the 4-position, 2-position, both at the 2- and 4- positions, and both the 2- and 6- positions. It is understood that there could be other isomers produced depending on Compound II, the halogenating agents and conditions used.
- the succinimide by-products are removed by any known means in the arts, such as washing the batch with water.
- the solvent e.g., toluene
- the solvent may be removed using any known methods such as distillation or vacuum.
- the solution of brominated, protected aniline (bromo-3,5- dimethoxytrifluoroacetanilide) in DMF is used in the cyanating step.
- the halogenating step comprises reacting 3,5- dimethoxytrifluoroacetanilide with at least one halogenating agent such as N-bromosuccinimide BS) in chlorobenzene to produce 2-bromo-3,5-dimethoxytrifluoroacetanilide and its isomers.
- the isomers may be removed or separated from solution before the cyanating step.
- the isomers are not removed or separated from solution before conducting subsequent reaction process.
- the protecting step and the selection of the protecting agent can improve the regioselectivity of Compound III.
- the protecting agent improves, or results in higher, regioselectivity of a 2-halo isomer of Compound III over the other isomers such as the 4-halo isomer.
- the halo moiety is bromo
- the process step wherein Compound IV is produced by the process comprising combining at least one Compound III with at least one cyanating agent to produce at least one Compound IV is referred to herein as the cyanating step.
- the cyanating step comprises combining the halo-isomers of the halogenating step with at least one cyanating agent to produce cyano-isomers.
- the bromo-isomers of Compound III including 2-bromo-3,5-dimethoxytrifluoroacetanilide, in DMF are combined with copper (I) cyanide at a temperature range from about 98°C to about 120 °C to produce
- K 4 Fe(CN)6 together with a suitable catalyst, such as Cul at greater than 100 mole%, is used as the cyanating agent.
- DMF is removed using any known means such as distillation to concentrate the batch.
- the concentrated DMF solution is transferred into a solution of ethylenediamine and water to perform the deprotecting step and removal of copper salts.
- Compound IV such as 2-amino-4,6-dimethoxybenzonitrile, is isolated by filtration and dried under a stream of nitrogen.
- the 2-isomer is isolated out of solution or precipitates out, while the non-favored isomers are not isolated out of the solution. It is an advantage of this invention that the desired isomer is isolated and the undesired isomers (4-, 2-/4-, and 2-/6- isomers), which are considered impurities, are not isolated.
- the cyanating step comprises precipitating 2-amino-4,6- dimethoxybenzonitrile.
- the process provided results in the precipitation of the desired 2- amino-4,6-dimethoxybenzonitrile intermediate product, resulting in lower isomeric impurities.
- the one-pot process improves cost and time factors for improved efficiency without the need to purify and isolate at each intermediate reaction.
- Compound IV is combined with at least one deprotecting agent and first precipitating agent, such as ethylenediamine and water.
- first precipitating agent such as ethylenediamine and water.
- the favored isomer i.e. 2-amino- 4,6-dimethoxybenzonitrile, precipitates out of solution while the other isomers remain in solution.
- the cyanating step can be carried out under any reaction time, pressure, temperature, solvent, pH condition, concentration, reagents ratio/amount, and any other chemical reaction conditions that are suitable to add at least one cyano (-CN) moiety to Compound III or replace at least one halo moiety with at least one cyano group on Compound III. It is understood that one skilled in the art can determine and/or optimize the reaction time, pressure, temperature, solvent, pH condition, concentration, reagent ratio/amount, and any other chemical reaction conditions suitable for the cyanating step.
- the temperature range for the cyanating step may be from about 50 °C to about 155 °C.
- the temperature range for the cyanating step may be from about 50 °C to about 120 °C.
- the temperature range for the cyanating step may be from about 50 °C to about 105 °C.
- the temperature range for the cyanating step may be from about 98 °C to about 105 °C.
- Cyanating agent refers to any compound which when reacted with Compound III can replace at least one halo moiety with a cyano group or add at least one cyano moiety to Compound III.
- Non-limiting examples of cyanating agent includes Zn(CN) 2 , CuCN, NaCN, KCN, Cu(CN) 2 , Ni(CN) 2 , iron cyanide and other agents of the like. Cyanating may be carried out with or without a catalyst, e.g., a cyanating agent may comprise a catalyst.
- the cyanating agent is CuCN.
- the cyanating agent comprises K 4 Fe(CN) 6 and Cul.
- the cyanating agent comprises Na 4 Fe(CN) 6 and CuBr.
- the cyanating agent comprises K 4 Fe(CN)6 and CuBr.
- the cyanating agent comprises Na 4 Fe(CN)6 and Cul.
- deprotecting refers to the removal of at least one protecting group or directing group.
- Deprotecting agent refers to any compound that can remove at least one protecting group or directing group.
- Non-limiting deprotecting agents include ethylenediamine, ammonia, ethanolamine, and methylamine.
- the deprotecting step is carried out before the cyanating step.
- the deprotecting step is carried out after the cyanating step.
- the deprotecting step is carried out simultaneously with the cyanating step.
- the deprotecting step can also be carried out partially before the cyanating step and/or partially during the cyanating step and/or partially after the cyanating step.
- any of the cyanating step and deprotecting step and precipitating step can be conducted in a one-pot process.
- the process step wherein the at least one Compound III is combined with at least one third precipitating agent, or wherein the at least one Compound IV is combined with at least one first or third precipitating agent, is referred to herein as the precipitating step.
- first precipitating agent refers to any substance that promotes or causes a Compound IV to precipitate out of solution.
- the resulting precipitate can comprise crystalline structures and/or amorphous structures.
- a non-limiting example of a suitable first precipitating agent is water. In light of the teachings of this specification, other suitable first precipitating agents will be familiar to those skilled in the art.
- third precipitating agent refers to any suitable non-polar solvent or other suitable substance that promotes or causes a Compound III or a Compound IV to precipitate out of solution.
- the resulting precipitate can comprise crystalline structures and/or amorphous structures.
- a non-limiting example of a suitable third precipitating agent is heptane.
- other suitable third precipitating agents will be familiar to those skilled in the art.
- deprotecting and precipitating are done in the same step.
- ethylenediamine and heptane are used to promote deprotecting and precipitating of Compound III.
- ammonia and heptane are used to promote deprotecting and precipitating of Compound III.
- ethanolamine and heptane are used to promote deprotecting and precipitating of Compound III.
- methylamine and heptane are used to promote deprotecting and precipitating of Compound III.
- ethylenediamine and water are used to promote deprotecting and precipitating of Compound IV.
- ammonia and water are used to promote deprotecting and precipitating of Compound IV.
- ethanolamine and water are used to promote deprotecting and precipitating of Compound IV.
- methylamine and water are used to promote deprotecting and precipitating of Compound IV.
- the precipitating step is carried out after the cyanating and deprotecting steps.
- second precipitating agent refers to any substance that promotes or causes a Compound IV to precipitate out of solution, following at least one previous precipitation of Compound IV with either a first precipitating agent or a third precipitating agent, in accordance with this invention.
- the resulting precipitate can comprise crystalline structures and/or amorphous structures.
- a non-limiting example of a suitable second precipitating agent is isopropyl alcohol. In light of the teachings of this specification, other suitable second precipitating agents will be familiar to those skilled in the art.
- the re-precipitating step may also result in purification of the Compound IV precipitate.
- the hydrating step comprises combining Compound IV with at least one hydrating agent and/or at least one hydrating catalyst to produce at least one
- Compound I is referred to herein as the hydrating step.
- the hydrating step reaction can be carried out under any reaction time, pressure, temperature, solvent, pH condition, concentration, reagents ratio/amount, and any other chemical reaction conditions that are suitable to remove or substitute at least one cyano moiety from Compound IV. It is understood that one skilled in the art can determine and/or optimize the reaction time, pressure, temperature, solvent, pH condition, concentration, reagent ratio/amount, and any other chemical reaction conditions suitable for the hydrating step.
- the hydrating step comprises converting at least one cyano moiety into at least one carboxamide.
- the hydrating step may be carried out at a temperature range from about 70 °C to about 150 °C.
- the hydrating step may be carried out at a temperature range from about 100 °C to about 115 °C.
- the process for the synthesis of 2-amino-4,6-dimethoxybenzamide comprises hydrating 2-amino-4,6-dimethoxybenzonitrile with at least one hydrating agent such as methanesulfonic acid.
- the hydrating step further comprises re-precipitating 2-amino-4,6- dimethoxybenzonitrile before contacting it with a hydrating agent.
- the reaction is conducted for about two hours of heating (approximately 1-2 hours at temperatures between 100-115 °C).
- hydrating the nitrile compound further comprises adding water and dichloromethane (DCM) to the acidic mixture.
- DCM dichloromethane
- the choice of solvent is not limited to the preceding examples, but is dependent on the structure of the compound of interest among other factors.
- One skilled in the art may use alternate solvents that do not react with the compound of interest, such as but not limited to ethyl acetate, isopropyl acetate, ether such as 2- methyltetrahydrofuran, alcohol such as isopropyl alcohol, and other solvents or combinations of solvents of the like.
- the hydrating step further comprises neutralizing the batch by contacting about 50% caustic and adjusting the pH range from about 3 to about 12.
- neutralizing agent may be used to adjust the pH as desired.
- the pH range may be from about 6.0 to about 8.0. In another embodiment, the pH range may be from about 6.5 to about 7.3.
- the hydrating step further comprises an extracting step.
- the extracting step comprises extracting the aqueous layer with DCM three times and the organic layer is washed twice with water to remove methanesulfonate salts. Distillation of
- dichloromethane occurs to reduce the overall batch volume and the batch is slowly cooled to a temperature range from about 23 °C to about 28 °C.
- MtBE is charged to the batch and it is further cooled down to a temperature range from about -5 °C to about 0 °C.
- the product 2- amino-4,6-dimethoxybenzamide is isolated by any means such as by filtration and dried under a stream of nitrogen.
- One skilled in the art may use another type of solvent for extraction that does not adversely affect the reactions such as isopropyl acetate, ethyl acetate, isopropyl alcohol, 2-methyltetrahydrofuran, or combinations thereof.
- a solvent exchange occurs until there is less than 1% halogenated solvent remaining in the pot.
- a non-halogenated solvent may be used following neutralization, thereby potentially eliminating the need for solvent exchange.
- the volume is reduced via distillation until the desired volume range of IP Ac, IPA, ethyl acetate, methyl THF, or alternate solvent is achieved.
- an appropriate anti- solvent such as MtBE or heptane, is optional. However, yield improvement is observed with an appropriate anti-solvent.
- 2-amino-4,6-dimethoxybenzamide is prepared comprising hydrating 2-cyano-3,5-dimethoxytrifluoroacetanilide with a hydrating agent such as
- the preparation of 2-amino-4,6-dimethoxybenzamide comprises
- Hydrating agent refers to any compound which when combined with Compound IV can convert at least one cyano group into a carboxamide group or hydrate the triple bond of the cyano group.
- Hydrating agent also includes hydrating catalysts.
- the term "hydrating catalyst” refers to any compound that promotes and/or assists in hydrating Compound IV to Compound I.
- Non-limiting examples of hydrating agents include water, ferric nitrate, alcohols, acids such as sulfuric acid, trifluoroacetic acid, methanesulfonic acid, phosphoric acid such as polyphosphoric acid, bases such as NaOH, KOH, cesium hydroxide, barium hydroxide, metal catalyst, the like, and combinations thereof.
- the hydrating step converts the cyano group into a carboxamide group while minimizing the amount of carboxylic acid produced.
- the hydrating step is carried out under acidic reaction conditions.
- the hydrating step may also be carried out under basic reaction conditions.
- the reactions of the synthetic methods claimed herein are carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
- a given reaction can be carried out in one solvent or in a combination of two of more solvents.
- suitable solvents for a particular reaction step can be selected by one skilled in the art.
- the functional groups or moieties of the present invention include substituted or non- substituted, protected or non-protected moiety.
- substituted or non- substituted, protected or non-protected moiety When a particular group is "substituted" that group may have one or more substituents, from one to five substituents, from one to three substituents, from one to two substituents, independently selected from the list of substituents.
- some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
- some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- Trifluoroacetic anhydride (185 g) was added over at least 1 hour maintaining a reaction temperature of 18-25 °C. The reaction was stirred for at least 1 hour and then checked by HPLC for reaction completion. Water (250 g) was loaded to the batch and the reaction was heated to 40-45 °C and stirred for at least 10 minutes. The agitation was stopped and the phases were separated. The bottom aqueous phase was removed and water (250 g) was loaded to the toluene product layer. The batch was stirred at 40-45 °C for at least 10 minutes and the phases were separated by removing the bottom aqueous phase.
- the 3,5-dimethoxytrifluoroacetanilide product toluene solution was then cooled to less than 0 °C in preparation for the bromo-3,5- dimethoxytrifluoroacetanilide step of the process.
- the solution was heated to reflux and toluene was distilled until a pot temperature of 125-140 °C was obtained.
- the batch was cooled to less than 80 °C under nitrogen and N',N'-dimethylformamide (DMF) (1215 g) was loaded to the pot.
- the batch was agitated and cooled to less than 80 °C. This solution was used in the 2-amino-4,6-dimethoxybenzonitrile step of the process.
- DMF N',N'-dimethylformamide
- the batch was held at 5-15 °C for 2 hours and then the 2-amino-4,6-dimethoxybenzonitrile product was isolated by filtration.
- the 2-amino-4,6-dimethoxybenzonitrile cake was washed with water to remove the mother liquor.
- the final wet cake was dried and analyzed by HPLC. The process produced 123 grams of 2- amino-4,6-dimethoxybenzonitrile product in a yield of 88% from the starting 3,5- dimethoxyaniline .
- the resulting slurry was cooled slowly to 0-5 °C over at least 2 hours.
- the batch was held at 0-5 °C for at least 0.5 hours and filtered to harvest the product.
- the 2-amino-4,6-dimethoxybenzonitrile cake was washed with isopropyl alcohol and dried in a vacuum oven at 50 °C and 22 inches of vacuum.
- the process produced 83.8 grams of purified 2-amino-4,6-dimethoxybenzonitrile in 84% yield.
- DCM/MtBE is 1:3.2; total volumes of solvent is 18.9).
- the batch was slowly cooled to between -5 °C and 5 °C over at least 3 hours.
- the batch was held for at least 1 hour between -5 °C and 0 °C.
- Precipitation was verified through collection of at least two samples from the liquor to determine the amount of 2-amino-4,6-dimethoxybenzamide remaining in solution.
- the batch was isolated by filtration and the wet cake washed with a cold (0 °C) mixture of 1:4
- alternate solvents include, but are not limited to esters like isopropyl acetate and ethyl acetate, and ethers like 2-methyltetrahydrofuran.
- alternate precipitation systems with or without anti- solvent have also been examined.
- the precipitation system may include, but is not limited to esters like isopropyl acetate, ethers like 2-methyltetrahydrofuran, and alcohols like isopropyl alcohol.
- the yield range from these modifications in the experimental procedure is 72-79%.
- purity of the desired compound is consistently over 99%.
- the first organic phase cut was performed.
- the aqueous layer was extracted two additional times with DCM (371 mL and 286 mL respectively).
- Dichloromethane (271 mL) was added to the combined organic layers and the organic layer was washed with water (714 mL) to remove methanesulfonate salts.
- Dichloromethane (79 mL) was added to the combined organic layers and the organic layer was washed once more with water (714 mL) to remove methanesulfonate salts.
- the batch was distilled using (5-10 inches Hg) vacuum to a pot volume of 6 volumes DCM (300 mL).
- Solvent exchange with isopropyl acetate was completed when less than 1-2% DCM remained and the pot volume was between 400-450 mL.
- the contents of the vessel were stirred for 1 hour at 85-90 °C.
- the vessel was cooled to 50 °C over at least 2 hours with slow agitation.
- the vessel was slowly charged with MtBE (250 mL) and the batch was agitated for 30 min at 50 °C.
- the batch was slowly cooled to 30 °C over at least 1 hour.
- the batch was cooled to -5 °C and 5 °C over at least 2 hours.
- the batch was held between -5 °C and 5 °C over at least 1 hour.
- a reaction sample was added to sodium thiosulfate solution and the organic layer analyzed by GC.
- Water 100.01 g was added to the reaction mixture and the mixture was agitated. The aqueous layer was removed and the organic layer was then washed twice more with water (101.08, and 100.94 g). The solvent was removed by rotary evaporation in vacuo to yield an off-white solid (63.04 g).
- Trifluoroacetic acid (6.52 g, 4.4 mL) was charged to a flask equipped with a magnetic stirring bar and thermocouple. Sulfuric acid (96%, 9.2 g, 5mL) was charged to the flask. In small portions 2-amino-4,6-dimethoxybenzonitrile (1.01 g, -76% pure) was charged to the mixed acid solution in the flask. A condenser was added and the solution was heated at 75 °C for 17 h. After the dark mixture had cooled to room temperature it was charged to water (9.79 g) cooled in a large ice bath while maintaining the reaction temperature below 10 °C. Concentrated ammonium hydroxide (19.37 g) was added dropwise to the cooled solution (reaction
- the batch was agitated and heated to 80 °C. External heating was removed and the batch cooled to 20-25 °C.
- the precipitated bromo-3,5- dimethoxytrifluoroacetanilide was isolated by filtration, washed with heptane (100 mL) and dried in a vacuum oven at 50 °C. The process produced 99.6 grams of bromo-3,5- dimethoxytrifluoroacetanilide in 93% yield.
- This example provides various conditions in accordance with the present invention for the conversion of 2-amino-4,6-dimethoxybenzonitrile to 2-amino-4,6-dimethoxybenzamide.
- the main routes for hydrating are: acidic, basic, and catalytic (involving a catalyst in addition to another reagent), or use of various groups of metals to facilitate the reaction.
- the reaction time varies. In the following conditions, the optimal reaction temperature range is from about 100 °C to about 115 °C, with reaction completion in 1 hour to 2 hours.
- 2-amino-4,6-dimethoxybenzonitrile (2-amino-4,6-dimethoxybenzonitrile), CH 3 SO 3 H, with or without A1 2 0 3 , workup with KOH and/or 50% caustic and/or phosphate buffer and/or 30% potassium carbonate at 120 °C for 2-4 hours. Product not isolated. Conversion to 2-amino- 4,6-dimethoxybenzamide: 78-88% (by HPLC).
- reactants and components referred to by chemical name or formula anywhere in this document, whether referred to in the singular or plural, are identified as they exist prior to coming into contact with another substance referred to by chemical name or chemical type (e.g., another reactant, a solvent, or etc.). It matters not what preliminary chemical changes, transformations and/or reactions, if any, take place in the resulting mixture or solution or reaction medium as such changes, transformations and/or reactions are the natural result of bringing the specified reactants and/or components together under the conditions called for pursuant to this disclosure.
- the reactants and components are identified as ingredients to be brought together in connection with performing a desired chemical operation or reaction or in forming a mixture to be used in conducting a desired operation or reaction.
- an embodiment may refer to substances, components and/or ingredients in the present tense ("is comprised of”, “comprises”, “is”, etc.), the reference is to the substance, component or ingredient as it existed at the time just before it was first contacted, blended or mixed with one or more other substances, components and/or ingredients in accordance with the present disclosure.
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